Endopeptidases exopeptidases

In addition, renal tubular cells contain various proteases for the degradation of proteins and oligopeptides. These enzymes are located predominantly in the lysosomes and micro-somes of these cells, but some have been reported on the brush-border membranes [16]. Degradative enzymes include various endopeptidases, exopeptidases and esterases [17]. 

Figure 1.11 Generic peptide showing points of cleavage by exopeptidases and endopeptidases. Exopeptidases cleave...

Proteolytic enzymes - hydrolyse proteins selectively, either on terminal groups (exopeptidases) or internal linkages (endopeptidases), eg... 

Gener ally, a family of peptidases contains either exopeptidases or endopeptidases, but there are exceptions. Family Cl contains not only endopeptidases such as cathepsin L, but also the aminopeptidase bleomycin hydrolase. Some members of this family can act as exopeptidases as well as endopeptidases. For example, cathepsin B also acts as a peptidyl-dipeptidase, and... 

There are two main classes of proteolytic digestive enzymes (proteases), with different specificities for the amino acids forming the peptide bond to be hydrolyzed. Endopeptidases hydrolyze peptide bonds between specific amino acids throughout the molecule. They are the first enzymes to act, yielding a larger number of smaller fragments, eg, pepsin in the gastric juice and trypsin, chymotrypsin, and elastase secreted into the small intestine by the pancreas. Exopeptidases catalyze the hydrolysis of peptide bonds, one at a time, fi"om the ends of polypeptides. Carboxypeptidases, secreted in the pancreatic juice, release amino acids from rhe free carboxyl terminal, and aminopeptidases, secreted by the intestinal mucosal cells, release amino acids from the amino terminal. Dipeptides, which are not substrates for exopeptidases, are hydrolyzed in the brush border of intestinal mucosal cells by dipeptidases. 

The end product of the action of endopeptidases and exopeptidases is a mixmre of free amino acids, di- and tripeptides, and oligopeptides, all of which are absorbed. Free amino acids are absorbed across the intestinal mucosa by sodium-dependent active transport. There are... 

Proteases, which can be classified as either peptidases or proteinases. These cleave polypeptide chains eventually into their component amino acids. Peptidases can be further classified as endopeptidases (which act on the main-chain amido groups along the polypeptide molecule) or as exopeptidases (which act only at terminal amino acid residues). 

As mentioned earlier, by far the largest number of zinc enzymes are involved in hydrolytic reactions, frequently associated with peptide bond cleavage. Carboxypeptidases and ther-molysins are, respectively, exopeptidases, which remove amino acids from the carboxyl terminus of proteins, and endopeptidases, which cleave peptide bonds in the interior of a polypeptide chain. However, they both have almost identical active sites (Figure 12.4) with two His and one Glu ligands to the Zn2+. It appears that the Glu residue can be bound in a mono- or bi-dentate manner. The two classes of enzymes are expected to follow similar reaction mechanisms. 

The NC-IUBMB classifies peptidases (EC 3.4) into exopeptidases (EC 3.4.11-19), which remove one or a few amino acids, and endopeptidases (proteinases, EC 3.4.21-99), which catalyze the cleavage of peptide bonds away from either end of the polypeptide chain (Fig. 2.1). Exopeptidases are further subdivided into enzymes that carry out hydrolysis at the N-terminus or the C-terminus (Figs. 2.1 and 2.2). Thus, aminopeptidases (EC 3.4.11) cleave a single amino acid from the N-terminus [3] those removing a dipep-... 

The NC-IUBMB has introduced a number of changes in the terminology following the proposals made by Barrett, Rawlings and co-workers [7] [8]. The term peptidase should now be used as a synonym for peptide hydrolase and includes all enzymes that hydrolyze peptide bonds. Previously the term peptidases was restricted to exopeptidases . The terms peptidase and protease are now synonymous. For consistency with this nomenclature, the term proteinases has been replaced by endopeptidases . To complete this note on terminology, we remind the reader that the terms cysteine endopeptidases and aspartic endopeptidases were previously called thiol proteinases and acid or carboxyl proteinases , respectively [9],... 

One of the general principles of the Nomenclature Committee is that enzymes should be classified and named according to the reaction they catalyze. However, the overlapping specificities of and great similarities in the action of different peptidases render naming solely on the basis of function impossible [10]. For example, some enzymes can act as both endo- and exopeptidases. Thus, cathepsin H (EC 3.4.22.16) is not only an endopeptidase but also acts as an aminopeptidase (EC 3.4.11), and cathepsin B (EC 3.4.22.1) acts as an endopeptidase as well as a peptidyl-dipeptidase (EC 3.4.15). The actual classification of peptidases is, therefore, a compromise based not only on the reaction catalyzed but also on the chemical nature of the catalytic site, on physiological function, and on historical priority. 

SC 6 Families of endopeptidases (oligopeptidases) and exopeptidases (including lysosomal carboxypeptidase A in family S10) Ser, Asp, His a,/3-Hydrolase... 

The evolutionary classification has a rational basis, since, to date, the catalytic mechanisms for most peptidases have been established, and the elucidation of their amino acid sequences is progressing rapidly. This classification has the major advantage of fitting well with the catalytic types, but allows no prediction about the types of reaction being catalyzed. For example, some families contain endo- and exopeptidases, e.g., SB-S8, SC-S9 and CA-Cl. Other families exhibit a single type of specificity, e.g., all families in clan MB are endopeptidases, family MC-M14 is almost exclusively composed of carboxypeptidases, and family MF-M17 is composed of aminopeptidases. Furthermore, the same enzyme specificity can sometimes be found in more than one family, e.g., D-Ala-D-Ala carboxypeptidases are found in four different families (SE-S11, SE-S12, SE-S13, and MD-M15). 

The proteolytic activity of some multicatalytic peptidases is stimulated by ATP, whereas that of others is not influenced by ATP [32], The ATP-dependent proteolytic system first found in reticulocytes requires the presence of a heat-stable polypeptide called ubiquitin, one of the roles of which is to mark particular proteins for subsequent degradation [33. ATP-Indepen-dent multicatalytic peptidases can degrade proteins that have a free amino or an /V-acctylatcd terminus, as well as oxidatively altered or phosphorylat-ed proteins [34], The small peptides generated are resistant to multicatalytic peptidases and are further degraded by cytoplasmic endopeptidases and exopeptidases. 

The in vitro hydrolysis of insulin has been shown to be catalyzed by exopeptidases and endopeptidases. Carboxypeptidase A (EC 3.4.17.1) cleaves the C-terminus of the B-chain (ThrB3°) and that of the A-chain (AsnA21) [145], Leucyl aminopeptidase (EC 3.4.11.1) cleaves the N-terminus of the B-chain (PheB1) and can continue to shorten it. But, leucyl aminopeptidase appears also able to cleave the N-terminus of the A-chain (GlyA1). In addition to these exopeptidases, entire insulin is also cleaved by endopeptidases of the... 

These structural changes did protect the peptide against exopeptidases, but left it sensitive to endopeptidases. Indeed, the compound was rapidly and... 

A novel concept of using bioadhesive polymers as enzyme inhibitors has been developed [97]. Included are derivatives of poly acrylic acid, polycarbophil, and car-bomer to protect therapeutically important proteins and peptides from proteolytic activity of enzymes, endopeptidases (trypsin and a-chymotrypsin), exopeptidases (carboxypeptidases A and B), and microsomal and cytosolic leucine aminopeptidase. However, cysteine protease (pyroglutamyl aminopeptidase) is not inhibited by polycarbophil and carbomer [97]. 

Protein digestion occurs in two stages endopeptidases catalyse the hydrolysis of peptide bonds within the protein molecule to form peptides, and the peptides are hydrolysed to form the amino acids by exopeptidases and dipeptidases. Enteropeptidase initiates pro-enzyme activation in the small intestine by catalysing the conversion of trypsinogen into trypsin. Trypsin is able to achieve further activation of trypsinogen, i.e. an autocatalytic process, and also activates chymotrypsinogen and pro-elastase, by the selective hydro-... 

These proteolytic enzymes are all endopeptidases, which hydrolyse links in the middle of polypeptide chains. The products of the action of these proteolytic enzymes are a series of peptides of various sizes. These are degraded further by the action of several peptidases (exopeptidases) that remove terminal amino acids. Carboxypeptidases hydrolyse amino acids sequentially from the carboxyl end of peptides. They are secreted by the pancreas in proenzyme form and are each activated by the hydrolysis of one peptide bond, catalysed by trypsin. Aminopeptidases, which are secreted by the absorptive cells of the small intestine, hydrolyse amino acids sequentially from the amino end of peptides. In addition, dipeptidases, which are structurally associated with the glycocalyx of the entero-cytes, hydrolyse dipeptides into their component amino acids. 

The proteolytic enzymes are classified into endopeptidases and exopeptidases, according to their site of attack in the substrate molecule. The endopeptidases or proteinases cleave peptide bonds inside peptide chains. They recognize and bind to short sections of the substrate s sequence, and then hydrolyze bonds between particular amino acid residues in a relatively specific way (see p. 94). The proteinases are classified according to their reaction mechanism. In serine proteinases, for example (see C), a serine residue in the enzyme is important for catalysis, while in cysteine proteinases, it is a cysteine residue, and so on. 

Proteins are first denatured by the stomach s hydrochloric acid (see p. 270), making them more susceptible to attack by the endopeptidases (proteinases) present in gastric and pancreatic juice. The peptides released by endopeptidases are further degraded into amino acids by exopeptidases. Finally, the amino acids are resorbed by the intestinal mucosa in cotransport with Na"" ions (see p. 220). There are separate transport systems for each of the various groups of amino acids. 

Several different proteases can attack a single protein at enzyme-selective amino-acid sequences. Proteases can be divided into two categories. Endopeptidases are enzymes that cleave peptide bonds between specific, nonterminal amino acids. There are endopeptidases specific for just about every amino acid. Exopeptidases are enzymes that cleave terminal peptide bonds at either the C-terminus or N-terminus. 

Kinins are metabolized rapidly (half-life < 15 seconds) by nonspecific exopeptidases or endopeptidases, commonly referred to as... 

The metalloproteases include both exopeptidases (e.g., angiotensin-converting enzyme, aminopeptidase-M, and carboxypeptidase-A) and endopeptidases (e.g.,... 

---